New research highlights the obesity-fighting properties of the ketogenic diet

A groundbreaking study recently published in Nature Metabolism has uncovered the protective effects of bile acids (BAs) induced by the ketogenic diet (KD) in the fight against obesity.

Obesity is linked to a myriad of health issues including cardiovascular diseases, cancer, diabetes, and non-alcoholic fatty liver disease. These associations underscore the urgent need for effective treatments to alleviate its extensive health impacts.

The ketogenic diet, recognised for its distinctive metabolic effects, has been proven beneficial in managing refractory epilepsy and other health disorders. Research indicates that changes in gut microbiota and metabolites might play a role in the diet’s protective properties against intestinal inflammation and seizures.

Although it’s clear that gut microbiota and metabolites are pivotal in the metabolic transformations elicited by KD in both rodents and humans, the specific microbes and metabolites responsible remain unidentified.

In the referenced study, the efficacy of KD in obesity prevention was demonstrated through an experimental setup involving mice. These mice were fed either a standard chow diet (CD) or a KD for seven weeks. Results indicated significant reductions in fasting glucose levels and body weight in those on KD. Metabolomics analysis further identified shifts in the metabolic profiles of the KD group, with increases in 22 metabolites and decreases in 18.

A subsequent experiment involved feeding mice with CD, KD, or a methionine-supplemented version of KD (KDM) over seven weeks. The addition of methionine to KD reversed the diet’s reductions in glucose levels and body weight and decreased six taurine-conjugated bile acids in serum. KD alone reduced levels of certain unconjugated BAs, which were restored by KDM.

When gut microbiota were depleted, differences in body weight and glucose levels between KD and KDM groups vanished, highlighting the role of microbiota in these effects. Faecal microbiota transplantation (FMT) from KD-fed to CD-fed mice resulted in weight loss and enhanced glucose tolerance. Conversely, FMT from KDM mice had no significant impact.

Further analyses showed that KD reduced the alpha diversity of gut microbiota, a change reversed by KDM. This diet also affected specific bacterial strains, which were restored by KDM supplementation. Studies on energy absorption revealed that KD-fed mice exhibited higher faecal energy content, suggesting a reduction in calorie absorption.

RNA sequencing of ileal tissues indicated that treatment with specific bile acids (TUDCA or TDCA) downregulated CAR1, a gene associated with obesity. These treatments also diminished lipid accumulation in cells, facilitated weight loss, and decreased intestinal lipid absorption in mice.

In models of diabetes and obesity, treatments with TUDCA and TDCA resulted in weight reduction, lower fasting glucose levels, improved glucose tolerance, and decreased liver fat. Human studies paralleled these findings, showing that lower plasma levels of certain conjugated BAs were associated with higher body mass index and fasting glucose levels.

In conclusion, this study illuminates the potential of the ketogenic diet and targeted bile acid treatments in managing obesity and improving metabolic health through modifications in gut microbiota and metabolic processes.

The findings highlight critical host-gut microbiota interactions and support the use of TUDCA and TDCA as potential therapeutic agents for tackling obesity and its associated complications.